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Studies on the Metabolism of the Novel Antitumor Agent [N-methyl-¹¹C]N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in Rats and Humans prior to Phase I Clinical Trials¹

MRC Cyclotron Unit. Royal Postgraduate Medical School. Hammersmith Hospital, Ducane Road, London W12 OHS [S. O., S. K. L., F. B., S. P. H., G. B., R. J. A. H., J. C. M., T. J., P. M. P.], and the Cancer Research Laboratory, University of Auckland, School of Medicine, Private Bag 92019, Auckland, New Zealand [W. A. D., B. C. B.]

This study reports on the biodistribution and metabolism of the ¹¹C-labeled novel antitumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (also known as NSC 601316) in rats (plasma and tissues) and humans (plasma). Information on plasma metabolites was uniquely obtained in humans prior to Phase I clinical trial following i.v. injection of [¹¹C]DACA at tracer dose.

DACA was labeled in the N-methyl position using no-carrier-added [¹¹C]iodomethane. Rapid high-performance liquid chromatography methods were developed for metabolite analysis of [¹¹C]DACA. The metabolism of [¹¹C]DACA was investigated in patients by plasma sampling. The biodistribution and metabolism of [¹¹C]DACA was investigated in rats by plasma sampling, sacrifice experiments with tissue analyses, and imaging using positron emission tomography scanning.

Analysis of human plasma demonstrated rapid and extensive metabolism of [¹¹C]DACA. The levels of [¹¹C]DACA changed from 77 ± 8% (SD) at 5 min to 25 ± 5% at 45 min postinjection. Seven radioactive metabolites were observed in human plasma, and one was identified as [¹¹C]DACA-N-oxide.

Rapid clearance of ¹¹C radioactivity from rat blood, plasma, and major organs was observed. The half-life of ¹¹C radioactivity clearance in rat blood between 15 and 90 min was calculated to be 3.2 h; the levels of [¹¹C]DACA in rat plasma decreased from 69 ± 3% (SD) at 2 min to 29 ± 1.5% at 25 min. The number of radioactive metabolites in rat plasma was the same as in human plasma except that the proportions differed. Again, one metabolite was identified as the [¹¹C]DACA-N-oxide. Analysis of rat tissues showed rapid and extensive metabolism in tissues, particularly liver and kidney; however, [¹¹C]DACA (i.e., the parent compound) was the major radioactive component in the lung, heart, and brain over 40 min. Positron emission tomography scanning using [¹¹C]DACA in the rat showed little retention of ¹¹C radioactivity in major organs with rapid excretion via gut and kidney. The rat data were consistent with animal (mouse and rat) preclinical data obtained with preexisting techniques with longer-lived isotopes.

Labeling of potential anticancer drugs with positron-emitting radionuclides and performing in vivo preclinical evaluation at tracer doses in animals and humans prior to Phase I clinical trials provides unique information that could speed up the assessment of the drug and could potentially assist drug development programs. In this example, there was no unexpected interspecies difference in metabolism of DACA that would have alerted us to make a change in the planned Phase I study.

¹ This work was supported by the Cancer Research Campaign Grant ST2 193/0101.

² To whom requests for reprints should be addressed.

Received 11/ 1/96. Accepted 4/ 2/97.

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